To answer this question we need to review the basics of the inhibitory constant (Ki) and I value mean. The inhibitory constant (Ki) is the concentration of the inhibitor that is required in order to decrease the maximal rate of the reaction by half.(1,2)  Therefore, the smaller the Ki, the smaller amount of medication needed in order to inhibit the activity of that enzyme.  If a Ki is much larger than the maximal plasma drug concentrations a patient is typically exposed to from typical dosing, then that drug is not likely to inhibit the activity of that enzyme.  The Ki can be used in the determining the [I]/Ki ratio as a tool for predicting drug-drug interactions.

The [I] represents the mean steady-state Cmax value of the inhibitor exposed to the active site of the enzyme in question (such as a cytochrome P-450 (CYP) enzyme).(1,2)  The closer the drug concentration is to the Ki the greater chance that the medication in question will inhibit that enzyme and cause drug interactions with medications that are substrates of that enzyme.  Therefore, as the ratio increases so is the likelihood of a drug interaction.  The United States Food and Drug Administration (FDA) has suggested the following approach for determining the likelihood of an interaction. If the [I]/Ki ratio is < 0.1 the prediction for a drug interaction is remote, if > 0.1 but < 1 it is possible and if the ratio is > 1 it is likely.(1)  As an example, let us consider the ability of proton pump inhibitors (PPI) to inhibit CYP3A4. It has been reported that the Ki's ranged from 42 to 51 mM for most PPIs and that their respective maximum concentrations ranged from 1 to 5.2 mM in patients who are either extensive metabolizers or poor metabolizers of 2C219 and have also received doses of PPIs commonly seen in practice.(3-9)  A basic assessment of the range in [I]/Ki ratios (0.02 - 0.11) would suggest that they are not likely to inhibit CYP3A4 and result in drug-drug interactions of substrates for CYP3A4.  This turns out to also be true clinically as well.  

The use of the [I] and the Ki is a good example for how clinicians can make predictions about the likelihood for a drug-drug interaction when no other information is available or that have not been classified appropriately in various drug interaction databases.  This will be easier for clinicians to also consider or evaluate as this continues to get incorporated into the product package inserts for various medications.(2,10)

1. United States Food and Drug Administration.  Guidance for Industry.  Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling.  September 2006. Clinical Pharmacology. Accessed last on 5/19/2009.
2. Bachmann KA, Lewis JD.  Predicting inhibitory drug-drug interactions and evaluating drug interaction reports using inhibition constants.  Ann Pharmacother  2005;39:1064-72.
3. Li XQ, Andersson TB, Ahlstrom M, Weidolf L.  Comparison of inhibitory effects of the proton pump inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities.  Drug Metab Dispos  2004;32:821-7.
4. Dexlansoprazole (Kapidex®) product package insert.  Takeda Pharmaceuticals America, Inc.  Deerfield, IL  January 2009.
5. Esomeprazole (Nexium®) product package insert.  AstraZeneca Pharmaceuticals LP.  Wilmington, DE.  June 2009.
6. Lansoprazole (Prevacid®) product package insert.  Takeda Pharmaceuticals America, Inc.  Deerfield, IL  January 2009.
7. Pantoprazole (Protonix®) product package insert.  Wyeth Pharmaceuticals Inc. Philadelphia, PA.  May 2008.
8. Rabeprazole (Aciphex®) product package insert.  Eisai Co., Ltd.  Tokyo, Japan.  January 2009.
9. Rodrigues AD, Lin JH.  Screening of drug candidates for their drug-drug interaction potential.  Curr Opin Chem Biol  2001;5:396-401.
10. Atazanavir (Reyataz®) product package insert.  Bristol-Myers Squibb.  Princeton, NJ.  April 2009.

Inhibitory constant, Ki, I/Ki Ratio, Ki Drug Interactions